Patent GB-899056-A (GB)
Title: Tertiary alcohols and esters thereof, and their use
Filed: 1960-04-22
Abstract: The invention comprises compounds of the formula <FORM:0899056/IV (b)/1> wherein one of R1 and R2 is a mono- or bicyclic heterocyclic radical of aromatic character which contains one or two nitrogen atoms as members of the heterocycle and which may contain as substituents alkyl or alkoxy groups of up to 5 carbon atoms or halogen atoms and the other is a similar heterocyclic radical or an aryl radical which may be substituted by alkyl, polyhalogenoalkyl, alkoxy, alkylenedioxy or alkylmercapto groups of 1 to 5 carbon atoms, or nitro or dialkylamino groups (in which each alkyl group contains at most 5 carbon atoms) or halogen atoms, R3 is a monocyclic aryl radical substituted by a group -O-A-Z (wherein A is an alkylene group and Z is an N,N-di-hydrocarbon amino group, each hydrocarbon radical containing at most 10 carbon atoms, or an N,N-alkylene-imino group in which the alkylene chain may be interrupted by a oxygen, nitrogen or sulphur atom and which may contain as substituents hydroxy, alkanoyloxy, hydroxyalkyl or alkanoyloxyalkyl groups) and optionally substituted by alkyl, alkoxy, alkylenedioxy, alkymercapto, nitro or polyhalogenoalkyl groups, or dialkylamino groups each alkyl group of which contains up to 5 carbon atoms, or additional groups-O-A-Z, or halogen atoms, R4 and R5 are hydrogen atoms or alkyl groups of at most 5 carbon atoms and R6 is a hydrogen atom or an acyl radical; and their acid-addition salts, quaternary ammonium derivatives and N-oxides.  They may be prepared by reacting a ketone XCOY with organometallic reagent Z-M+, one of the radicals X, Y and Z being R2, another being R3 and the third being -CR1.R4.R5, and M+ being a positively charged ion of a metal of Group Ia of the Periodic System or the positively charged ion of the formula Met-Hal+ in which Met is a bivalent metal of Group II of the Periodic System and Hal is a halogen atom (which reagents are prepared by known methods), and, if desired, acylating the product.  Products which are mixtures of racemates may be separated by standard procedures and separated racemates may be resolved into optically active forms. Detailed examples are given and extensive lists of salt-forming organic and inorganic acids and quaternizing agents are provided.  Ketones of the formula R2COR3 wherein R3 has the meaning given above and R2 is a monocyclic heterocyclic radical are prepared from the acid halide R2.CO.Hal and a compound of the formula R3H or one of the formula R31H, wherein R31 is radical capable of being converted into the radical R3, in presence of a Friedel Crafts catalyst and, if necessary, converting R31 to R3.  Ketones of the formula <FORM:0899056/IV (b)/2> (wherein R2 is pyridyl, and A and Z are defined above) and salts thereof, are prepared by treating an ester R2COOPh with a strong inorganic Lewis acid and reacting the resulting ketone of the formula <FORM:0899056/IV (b)/3> preferably as an alkali metal salt, with the halide Hal-A-Z.  4 - (2 - N, N - diethylaminoethoxy) - 41 - methoxy-benzophenone is prepared by heating phenyl 4-methoxy-benzoate with aluminium chloride in nitrobenzene to give 4-hydroxy-41-methoxy-benzophenone and reacting the sodium salt of this with 2-N,N-diethylaminoethyl chloride to give the hydrochloride of the required product, from which the free base is subsequently liberated.  4 - (2 - N, N - diethylaminoethoxy) - phenyl 3-pyridyl ketone is prepared by reacting nicotinic acid with thionyl chloride to give nicotinoyl chloride, reacting this with anisole to give 4-methoxy-phenyl 3-pyridyl ketone, refluxing this with hydrobromic acid to give 4-hydroxy-phenyl 3-pyridyl ketone and reacting the sodium salt of this with 2-N,N-diethylaminoethyl chloride.  The corresponding N,N-dimethyl compound and 4 - (2 - N, N - diethylaminoethoxy) phenyl - 4 - pyridyl ketone are prepared similarly.  4 - (2 - N, N - diethylaminoethoxy) - phenyl 2-pyridyl-methyl ketone is prepared by reacting a -picoline lithium with methyl 4-(2-N,N-diethylaminoethoxy)-benzoate.  Compounds of the formula M+.C.R.1.R4R5-wherein R4 and R5 are as defined above, R1 is a monocyclic heterocyclic radical and M+ is the positive ion of an alkali metal are prepared by reacting the compound CH.R1.R4.R5 with an organic alkali metal compound, such as an alkyl or aryl alkali metal compound.  Compounds of the formula M+C.R1.R4.R5-wherein R1 is a monocyclic aryl radical, at least one of R4 and R5 is an alkyl group and M+ is the positive ion of an alkali metal are prepared by treating at a low temperature a solution of an ether of the formula Y-O-C.R1R4.R5 (Y being alkyl, aryl or the radical -C.R1.R4.R5 with an alkali metal  The compounds of the invention, which are stated to exhibit anti-uterotropic or anti-estrogenic effects, may be formulated as pharmaceutical compositions suitable for enteral or parenteral administration.  These may take the form of tablets capsules, dragees, solutions, suspensions or emulsions, and may contain preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.